Fever: role of pyrogens and cryogens.
The biology of cytokines is one of the most rapidly growing areas of biomedical research. It is understandable why the assumption was made several years ago that EP was equivalent to IL-1 (both alpha and beta) and subsequently to IL-1 alpha, IL-1 beta, and TNF. However, as more data have been obtained, it has become clearer that many cytokines and hormones are capable of participating in the febrile response. It is also becoming apparent that EPs and ECs might influence body temperature during nonpathological states, perhaps contributing to the elevation in temperature during or after exercise, the circadian variation in temperature, and others. Medical textbooks have begun to list IL-1 as the EP. As I attempted to make clear in this review, evidence that IL-1 alpha is a circulating EP is poor. The evidence is considerably stronger that IL-1 beta is an EP, at least during LPS-induced fever in rodents. The point I have tried to emphasize is that before any cytokine or hormone can be characterized as an EP or EC (or, for that matter, as being involved in any of the acute phase responses), clearly established rules must be followed, which are patterned after the traditional criteria used by Koch to distinguish a pathogenic microorganism from a benign one. As summarized in Tables 4 and 5, there are many candidates for EPs and ECs, but much more experimental evidence is essential before we gain a clear understanding of the relationship between contact with an exogenous pyrogen, the release of EPs and ECs, and the development of fever.